Methods, systems and apparatus for manipulating particles

ABSTRACT

An apparatus for manipulating particles includes: a rotor rotatable at a speed about an axis, the rotor having an outer periphery and front and rear opposite sides; at least one chamber mounted on the rotor, each chamber having an inlet and an outlet; an umbilical assembly rotatable about the axis; and a drive mechanism configured to rotate the umbilical assembly at about one-half the speed of the rotor. The umbilical assembly includes: a curvilinear guide tube connecting to a drum at the rear side of the rotor; a flexible conduit residing in the guide tube; and first and second elongate passageways for each chamber extending through the conduit, wherein the first passageway is in fluid communication with the inlet of a respective chamber and the second passageway is in fluid communication with the outlet of the respective chamber. The passageways are held in a spaced-apart relationship relative to one another.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/499,807, filed Jul. 16, 2012, which is a 35 U.S.C. § 371 nationalphase application of PCT International Application No.PCT/US2010/051631, filed Oct. 6, 2010, which claims priority from U.S.Provisional Patent Application No. 61/249,058, filed Oct. 6, 2009, thedisclosures of which are hereby incorporated herein by reference intheir entireties.

FIELD OF THE INVENTION

The present invention is related to methods, systems, and apparatus thatare used for transferring and manipulating particles, as well ascomponents that are useful in systems and apparatus for transferring andmanipulating particles, such as continuous flow centrifuges.

BACKGROUND

Conventional continuous flow centrifuges raise several concerns withregard to leaking and/or contamination. For example, in conventionalcontinuous flow centrifuges, when a length of tubing is fixedly attachedto the rotation axis of a device which contains the fluid material to becentrifuged, the entire length of tubing must be rotated by use ofrotating seals or other means to avoid twisting the tubing. However,these seals too frequently become the source of leaks and/orcontamination.

Umbilical-like arrangements for use with continuous flow centrifugeshave been disclosed in, for example, U.S. Pat. Nos. 4,216,770,4,419,089, 4,389,206, and 5,665,048. However, these solutions do notadequately address the high stresses and strains imparted on the tubesdue to the g-forces created by rotating the centrifuge at high speedsand/or due to the continuous fluid flow necessary to substantiallyimmobilize particles. Moreover, rotating the centrifuge at high speedscreates increased “partial” twisting action of the umbilical system andthe tubes contained therein, and the arrangements disclosed to date donot allow the umbilical system and the tubes contained therein to berotated at a high rate of speed for an acceptable amount of time beforefailing. In other words, it is believed that the aforementionedsolutions simply do not allow the systems to be “scaled up” to anappreciable degree and do not allow the system to be rotated at highrates of speed without rapid and catastrophic failure of the tubingsystem.

For small-scale operations, the elimination of rotary seals or the likemay address some contamination concerns with regard to conventionalcontinuous flow centrifuges. However, other contamination concernsremain. For example, the fluid flow paths may become contaminated overtime (e.g., after more than one use), unless the utmost care is taken incleaning and/or sterilization. A disposable fluid flow path (or multipledisposable fluid flow paths) could eliminate the need for expensive andtime-consuming cleaning, and could help ensure contamination-freeoperations. The disposable fluid flow paths would preferably be easilyreplaceable, and would be adaptable to a system that would allow thesystem as a whole to be “scaled-up,” as discussed above.

SUMMARY

According to some embodiments of the present invention, an apparatus formanipulating particles includes: a rotor rotatable at a speed about anaxis, the rotor having an outer periphery and front and rear oppositesides; at least one chamber mounted on the rotor, each chamber having aninlet and an outlet; an umbilical assembly rotatable about the axis; anda drive mechanism configured to rotate the umbilical assembly at aboutone-half the speed of the rotor. The umbilical assembly includes: acurvilinear guide tube connecting to a drum at the rear side of therotor; a flexible conduit residing in the guide tube; first and secondelongate passageways for each chamber extending through the conduit,wherein the first passageway is in fluid communication with the inlet ofa respective chamber and the second passageway is in fluid communicationwith the outlet of the respective chamber. The passageways are held in aspaced-apart relationship relative to one another.

In some embodiments, the first and second passageways for each chambercomprise corresponding first and second flexible tubes that extendthrough at least a major portion of a length of the conduit. Pottingmaterial within the conduit is configured to hold the tubes in thespaced-apart relationship relative to the one another and hold the tubesin a spaced-apart relationship relative to the conduit. The pottingmaterial may be further configured to restrict movement of the tubesrelative to the conduit and/or restrict movement of the tubes relativeto one another.

In some embodiments, the umbilical assembly further includes a flexiblemember extending through at least a major portion of a length of theconduit, wherein the flexible member extends substantially along acenterline of the conduit, and wherein the flexible tubes surround theflexible member. The potting material may be further configured torestrict movement of the tubes relative to the flexible member.

Each chamber may be a flexible translucent or transparent fluid chamber,and the apparatus may further include at least one chamber holderpivotably mounted to the front side of the rotor, wherein each chamberholder is configured to releasably enclose a respective chamber. Eachchamber holder may include a window to allow visual access to theenclosed chamber.

Each chamber may include a substantially conical body portion and aflange extending about at least a portion of a perimeter of the conicalbody portion. The flange includes an inlet fluid path and an outletfluid path, wherein the first flexible tube connects with the flangeinlet fluid path of a respective chamber and the second flexible tubeconnects with the flange outlet fluid path of the respective chamber.The flange inlet and outlet paths may be substantially parallel along asegment extending from a point at which the first and second tubesconnect with the flange inlet and outlet paths.

In some embodiments, the conduit and passageways are integrated as aflexible extrusion with an outer wall and internal elongate channelsthat define the spaced-apart passageways.

Each chamber may include a substantially conical body portion and aflange extending about at least a portion of a perimeter of the conicalbody portion. The flange includes an inlet fluid path and an outletfluid path, wherein the first passageway is in fluid communication withthe flange inlet fluid path of a respective chamber and the secondpassageway is in fluid communication with the flange outlet fluid pathof the respective chamber. A first tube may connect the first passagewayand the flange inlet fluid path and a second tube may connect the secondpassageway and the flange outlet fluid path, and the flange inlet andoutlet paths may be substantially parallel along a segment extendingfrom a point at which the first and second tubes connect with the flangeinlet and outlet paths. A connector may be included at each of the firstand second passageways, with one connector configured to connect thefirst tube with the first passageway and the other connector configuredto connect the second tube with the second passageway.

The drive mechanism may include gears. The gears may be at leastpartially enclosed by the drum. The conduit may include proximal anddistal opposite ends, wherein the conduit distal end connects to therotor. In some embodiments, the conduit distal end has a substantiallyhexagonally shaped coupling.

In some embodiments, the umbilical assembly includes a plurality ofspaced-apart flexible holders in the conduit to hold the passageways inthe spaced-apart relationship.

In some embodiments, the at least one chamber comprises a plurality ofchambers mounted on the rotor in a spaced-apart relationship.

According to other embodiments of the present invention, a disposablefluid path for use with a continuous flow centrifuge including a rotorhaving an outer periphery and front and rear opposite sides includes: atleast one chamber mounted on the rotor, each chamber having an inlet andan outlet; a flexible conduit curving around the outer periphery of therotor and connecting to the rotor; first and second flexible tubes foreach chamber extending through the conduit, wherein the first tube is influid communication with the inlet of a respective chamber and thesecond tube is in fluid communication with the outlet of the respectivechamber; and potting material within the conduit, wherein the pottingmaterial is configured to hold the tubes in a spaced-apart relationship.The potting material may be further configured to restrict movement ofthe tubes relative to the conduit and/or relative to one another.

In some embodiments, the disposable fluid path further includes aflexible member extending through the conduit, wherein the flexiblemember extends substantially along a centerline of the conduit, andwherein the flexible tubes surround the flexible member. The pottingmaterial may be further configured to restrict movement of the tubesrelative to the flexible member.

According to other embodiments of the present invention, an umbilicalassembly for use with a continuous flow centrifuge having a rotor and atleast one chamber having an inlet and an outlet attached to the rotorincludes: a curvilinear guide tube connecting to a drum at the rear sideof the rotor; a flexible conduit residing in the tube; first and secondflexible tubes for each chamber extending through at least a majorportion of a length of the conduit, wherein the first tube is in fluidcommunication with the inlet of a respective chamber and the second tubeis in fluid communication with the outlet of the respective chamber; andpotting material within the conduit, wherein the potting material isconfigured to hold the tubes in a spaced-apart relationship. The pottingmaterial may be further configured to restrict movement of the tubesrelative to the conduit and/or relative to one another.

In some embodiments, the umbilical assembly further includes a flexiblemember extending through the conduit, wherein the flexible memberextends substantially along a centerline of the conduit, and wherein theflexible tubes surround the flexible member. The potting material may befurther configured to restrict movement of the tubes relative to theflexible member.

According to other embodiments of the present invention, an umbilicalassembly for use with a continuous flow centrifuge having a rotor and atleast one chamber attached to the rotor includes a flexible extrusioncomprising first and second spaced-apart passageways therein for eachchamber, wherein the first passageway is in fluid communication with aninlet of a respective chamber and the second passageway is in fluidcommunication with an outlet of the respective chamber.

According to other embodiments of the present invention, a disposablefluid path for use with a continuous flow centrifuge having a rotorincludes a first disposable section and a second disposable section. Thefirst disposable section includes: at least one chamber configured to beheld on the rotor, wherein each chamber has an inlet and an outlet; andfirst and second tubes for each chamber, wherein the first tube isconfigured to be in fluid communication with the inlet of a respectivechamber and the second tube is configured to be in fluid communicationwith the outlet of the respective chamber. The second disposable sectionincludes: tubing in fluid communication with at least one container; thetubing configured to fit within one or more valves.

In some embodiments, the first disposable section includes return tubingin fluid communication with the at least one container. In someembodiments, the second disposable section includes return tubing influid communication with the at least one container. The first andsecond disposable sections may be configured to be connected using asterile tube welding process.

In some embodiments, each chamber is a flexible translucent ortransparent fluid chamber, wherein the chamber includes a substantiallyconical body portion. The chamber also includes a flange extending aboutat least a portion of a perimeter of the substantially conical bodyportion, and the flange includes an integral inlet fluid path and anintegral outlet fluid path. The first tube connects with the flangeinlet fluid path of a respective chamber and the second tube connectswith the flange outlet fluid path of the respective chamber. The flangeinlet and outlet fluid paths may be substantially parallel along asegment extending from the point at which the first and second tubesconnect with the flange inlet and outlet fluid paths.

According to other embodiments of the present invention, a centrifugalfluid processing system includes: a housing having an interior cavitywith an access aperture extending from an external surface of thehousing to the interior cavity; a plurality of fluid chambers held inspaced apart relationship on a rotor in the interior cavity; a flexibleconduit holding a plurality of flexible tubes in a spaced-apartrelationship therein, the flexible conduit extending from a locationthat is external to the housing through the access aperture and into theinterior cavity, wherein the plurality of tubes includes first andsecond tubes for each chamber, wherein the first tube is in fluidcommunication with an inlet of a respective chamber and the second tubeis in fluid communication with an outlet of the respective chamber,wherein the flexible conduit comprises a solid flexible material thatsubstantially fills an internal volume of the conduit and surrounds theflexible tubes, with the solid flexible material configured to hold theflexible tubes in the spaced-apart relationship; a substantially rigidcurvilinear guide tube holding a portion of the flexible conduit in theinterior cavity; and a drive mechanism configured to rotate the guidetube at a first speed and the rotor and the fluid chambers at a secondspeed, wherein the second speed is about twice the first speed.

According to other embodiments of the present invention, a centrifugalfluid processing system includes: a housing having an interior cavitywith an access aperture extending from an external surface of thehousing to the interior cavity; a plurality of fluid chambers held inspaced apart relationship on a rotor in the interior cavity; a flexibleconduit including a plurality of spaced-apart passageways therein, theflexible conduit extending from a location that is external to thehousing through the access aperture and into the interior cavity,wherein the plurality of tubes includes first and second passageways foreach chamber, wherein the first passageway is in fluid communicationwith an inlet of a respective chamber and the second passageway is influid communication with an outlet of the respective chamber; asubstantially funnel-shaped support with an open center passage, thesupport having a shape that tapers outward as it extends further intothe interior cavity, wherein the support surrounds the flexible conduitwith a centerline of the funnel shaped support being in line with acenterline of the access aperture; a substantially rigid curvilinearguide tube holding a portion of the flexible conduit in the interiorcavity; and a drive mechanism configured to rotate the guide tube at afirst speed and the rotor and the fluid chambers at a second speed,wherein the second speed is about twice the first speed.

According to other embodiments of the present invention, a centrifugalfluid processing system includes: a housing having an interior cavitywith an access aperture extending from an external surface of thehousing to the interior cavity; a plurality of flexible translucent ortransparent fluid chambers having an inlet and an outlet held inspaced-apart relationship on a rotor in the interior cavity, whereineach chamber includes a substantially conical body portion, each chamberincluding a flange extending about at least a portion of a perimeter ofthe conical body portion, the flange including an inlet fluid path andan outlet fluid path, wherein the flange inlet fluid path is in fluidcommunication with the inlet of the chamber and the flange outlet fluidpath is in fluid communication with the outlet of the chamber; aflexible conduit including a plurality of elongate spaced-apartpassageways therein, the flexible conduit extending from a location thatis external to the housing through the access aperture and into theinterior cavity, wherein the plurality of passageways includes first andsecond passageways for each chamber, and wherein the first passageway isin fluid communication with the flange inlet fluid path of a respectivechamber and the second passageway is in fluid communication with theflange outlet fluid path of the respective chamber; a substantiallyrigid curvilinear guide tube holding a portion of the flexible conduitin the interior cavity; a drive mechanism configured to rotate the guidetube at a first speed and the rotor and the fluid chambers at a secondspeed, wherein the second speed is about twice the first speed; and aplurality of substantially rigid chamber holders in the interior cavity,each sized and configured to releasably hold a respective flexiblechamber attached to the rotor.

According to other embodiments of the present invention, a method ofmanipulating particles includes providing: at least one chamber on arotor having an outer periphery, each chamber having an inlet and anoutlet; a flexible conduit with first and second spaced-apartpassageways therein for each chamber, wherein the first passageway is influid communication with the inlet of a respective chamber and thesecond passageway is in fluid communication with the outlet of therespective chamber; and a substantially rigid curvilinear guide tubeholding a portion of the conduit therein and curving around the outerperiphery of the rotor. The method further includes: rotating the rotorand the at least one chamber at a first speed, thereby creating acentrifugal force field; rotating the guide tube and conduit therein ata second speed, wherein the second speed is about one-half the firstspeed, thereby inhibiting the first and second passageways for eachchamber from fully twisting; flowing media and particles into arespective chamber using the first passageway, wherein a continuous flowof media and particles creates a fluid force that substantially opposesthe centrifugal force field, thereby immobilizing at least some of theparticles in a fluidized bed in the respective chamber; and flowingmedia out of the respective chamber and through the second passageway.

It is noted that aspects of the invention described with respect to oneembodiment, may be incorporated in a different embodiment although notspecifically described relative thereto. That is, all embodiments and/orfeatures of any embodiment can be combined in any way and/orcombination. Applicant reserves the right to change any originally filedclaim or file any new claim accordingly, including the right to be ableto amend any originally filed claim to depend from and/or incorporateany feature of any other claim although not originally claimed in thatmanner. These and other objects and/or aspects of the present inventionare explained in detail in the specification set forth below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a side perspective view of a system according to someembodiments of the present invention.

FIG. 2 is an opposing side perspective view of the system of FIG. 1.

FIG. 3 is a side perspective view of an interior portion of the systemof FIG. 1, illustrating internal components.

FIG. 4 is a side perspective view of an interior portion of the systemof FIG. 1, illustrating internal components.

FIG. 5A illustrates a chamber for use in systems and assembliesaccording to some embodiments of the present invention.

FIG. 5B illustrates a chamber holder for use in systems and assembliesaccording to some embodiments of the present invention.

FIG. 6 illustrates a chamber and chamber holder in position in thesystem of FIG. 1 according to some embodiments of the present invention.

FIG. 7 is a top perspective view of a disposable chamber according tosome embodiments of the present invention.

FIG. 8 is a perspective view of an umbilical assembly according to someembodiments of the present invention.

FIG. 9A is cross-sectional view of a portion of an umbilical assemblyaccording to some embodiments of the present invention.

FIG. 9B illustrates a portion of an umbilical assembly according to someembodiments of the present invention and FIG. 9C is a cross-sectionalview of the umbilical assembly of FIG. 9B.

FIG. 10 is a perspective view of an umbilical assembly according to someembodiments of the present invention.

FIG. 11 is a perspective view illustrating the umbilical assembly ofFIG. 10 connecting with a drum.

FIG. 12 is a perspective view illustrating a drive mechanism associatedwith the umbilical assembly of FIG. 10.

FIG. 13 is a top view of an umbilical assembly according to someembodiments of the present invention.

FIG. 14A is a perspective view of a funnel-shaped ingress/egress portfor use with an umbilical assembly according to some embodiments of thepresent invention.

FIG. 14B illustrates a clamp for use with an umbilical assemblyaccording to some embodiments of the present invention.

FIG. 14C is a perspective view of a funnel-shaped ingress/egress portfor use with an umbilical assembly according to some embodiments of thepresent invention.

FIG. 14D illustrates a funnel-shaped ingress/egress port for use with anumbilical assembly according to some embodiments of the presentinvention.

FIG. 15 is a perspective view of a system including disposable flowpaths according to some embodiments of the present invention.

FIG. 16 is another perspective view of the system of FIG. 15.

FIG. 17 is flow diagram illustrating operations according to someembodiments of the present invention.

FIGS. 18-20 are simulated screenshots of a display associated withsystems according to some embodiments of the present invention.

FIG. 21 illustrates a portion of an umbilical assembly according to someembodiments of the present invention.

DETAILED DESCRIPTION AND EMBODIMENTS OF THE INVENTION

The present invention now is described more fully hereinafter withreference to the accompanying drawings, in which some embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein; rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Like numbers refer to like elements throughout. In the figures, thethickness of certain lines, layers, components, elements or features maybe exaggerated for clarity.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, steps, operations, elements, components, and/or groupsthereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

It will be understood that when an element is referred to as being “on”,“attached” to, “connected” to, “coupled” with, “contacting”, etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on”, “directly attached” to, “directly connected”to, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “adjacent” another feature may have portions thatoverlap or underlie the adjacent feature.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if the device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of “over” and “under”. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Apparatus, systems, and methods for the manipulation of particles aredisclosed herein. Also, components useful in apparatus and systems forthe manipulation of particles are disclosed herein.

FIGS. 1 and 2 illustrate a system 10 according to some embodiments ofthe present invention. The system 10 includes an enclosure or housing 15and a door 20. The door 20 provides access to the internal components ofthe system 10, which are described in more detail below. The door 20 mayinclude a window 25 to provide visual access to the internal components.The door 20 can be hingedly attached to the enclosure 15, and can beopened by a handle 30, for example.

The system 10 includes a flange 35. The flange 35 may be included withthe door 20, or may be a separate component (i.e., when the door 20 isopened, the flange 35 remains in place). The flange 35 includes anaccess aperture 40, through which conduit with channels, passageways, ortubing therein, for example, can extend, as described in more detailbelow. The door 20 and/or the flange 35 can include a clamp 42, which isconfigured to hold the conduit in place and/or release the conduit.

FIG. 3 illustrates the system 10 with the door 20 opened. As shown, theflange 35 remains in place. FIG. 4 illustrates the system 10 with thedoor 20 and the flange 35 pivotably opened. The enclosure or housing hasan interior cavity 44, which can be seen in FIGS. 3 and 4 when the door20 and/or the flange 35 have been opened. Some of the internalcomponents of the system 10 are contained in the interior cavity 44, asseen in FIGS. 3 and 4. Notably, a rotor 45 is configured to be rotatableabout an axis. At least one fluid chamber 50 is attached to or mountedon the rotor 45, so as to be held in a fixed spaced-apart relationshipand rotate in response to rotation of the rotor 45. In some embodiments,a plurality of chambers 50 are attached to or mounted on the rotor 45;in the illustrated embodiment, four chambers 50 are present.

An exemplary chamber 50 is illustrated in more detail in FIG. 5A. Thechamber 50 may be substantially cone-shaped or may include asubstantially cone-shaped portion, as illustrated, although other shapesare contemplated including, for example, cylindrical, rectangular,frustoconical, pyramidal, etc. The chamber 50 includes an inlet 55 andan outlet 60. The chamber 50 is typically attached to or mounted on therotor 45 such that inlet 55 is situated toward the outer periphery ofthe rotor 45, and the outlet 60 is typically situated toward the centerof the rotor 45 (see FIG. 6). The chamber 50 may be mounted on the rotor45 such that the inlet 55 is situated proximate the outer periphery ofthe rotor 45 and the outlet 60 is situated proximate an inner radialportion of the rotor 45. The chamber 50 is configured to allow fluidflow therethrough while the rotor 45 and the chamber 50 rotate about anaxis. The force of fluid flowing from the inlet 55 to the outlet 60 cansubstantially oppose a centrifugal force created by the rotation of therotor 45 and the chamber 50. In this regard, particles can besubstantially immobilized in the chamber 50, such as in a fluidized bedin the chamber 50, by use of the summation of forces acting on theparticles. This action is described in more detail in U.S. Pat. Nos.5,622,819; 5,821,116; 6,133,019; 6,214,617; 6,334,842; 6,514,189;6,660,509; 6,703,217; 6,916,652; 6,942,804; 7,029,430; and 7,347,943;and U.S. Patent Application Publication Nos. 2005/0266548 and2008/0264865, the disclosure of each of which is hereby incorporated byreference in its entirety.

In some embodiments of the present invention, and as illustrated in thefigures, the rotor 45 may rotate in a plane substantially coaxial withthe gravitational axis (i.e., the rotor may rotate about a substantiallyhorizontal axis). Particles are substantially immobilized within afluidized bed within the chamber 50 by use of the summation of thevector forces acting on each particle. Embodiments of such apparatushave been disclosed in U.S. Pat. Nos. 5,622,819; 5,821,116; 6,133,019;6,214,617; 6,660,509; 6,703,217; 6,916,652; 6,942,804; 7,347,943; andU.S. Patent Application Publication Nos. 2005/0266548 and 2008/0264865,the disclosure of each of which is hereby incorporated by reference inits entirety. Though cells and particles are light in weight, their massis non-zero. Consequently, gravity has a significant effect on thesuspended particle or cell, and this effect will increase with time. Theweight of the suspended particles or cells causes these particles tosettle to the lowest regions of the container, disrupting the balance offorces which initially suspended them in the chamber. As is seen inprior art devices, particles tend to aggregate and the aggregation ofthese particles into a larger particle results in an increasedcentrifugal effect which causes the aggregates to migrate to longerradii, eventually causing destabilization of the fluidized bed.

In some other embodiments of the present invention, the rotor 45 mayrotate in a plane substantially transverse to the gravitational axis. Inthis regard, the rotor 45 may rotate about a substantially verticalaxis. Embodiments of such apparatus have been disclosed in U.S. Pat.Nos. 4,939,087; 5,674,173; 5,722,926; 6,051,146; 6,071,422; 6,334,842;6,354,986; 6,514,189; 7,029,430; 7,201,848; and 7,422,693, thedisclosure of each of which is hereby incorporated by reference in itsentirety. Particles are substantially immobilized within a fluidized bedwithin the chamber 50 by use of the summation of the vector forcesacting on each particle. More particularly, the flow of liquid mediaacts to create a force which opposes the centrifugal force field createdby the rotating chamber(s).

In still other embodiments, the rotor may rotate about any axis betweena horizontal axis and a vertical axis, including, for example, asubstantially horizontal axis.

Referring again to FIG. 5A, the chamber 50 may include a substantiallyconical body portion 71, and a flange 72 that surrounds at least aportion of the conical body portion 71 and/or that extends about atleast a portion of a perimeter of the conical body portion 71 (e.g., theflange 72 defines a plane that “wraps around” at least a portion of thechamber 50 and/or the conical body portion 71). The chamber inlet 55 maybe at an apex of the conical body portion 71. The chamber outlet 60 maybe proximate a base of the conical body portion 71. As illustrated, thechamber 50 includes inlet and outlet fluid paths 65, 70 which may beintegrated with the flange 72 of the chamber 50. The inlet fluid path 65may be external to the conical body portion 71 and may extend around atleast a portion of the perimeter of the conical body portion 71. Asdescribed in more detail below, tubes may connect with the flange inletand outlet fluid paths 65, 70. In these embodiments, the flange inletand outlet fluid paths 65, 70 may include substantially parallelsegments 73, 74 extending from the point at which the tubes connect withthe flange inlet and outlet fluid paths 65, 70.

The chamber 50 may fit within a holder, such as the chamber holder 75illustrated in FIG. 5B. The chamber holder 75 can carry all or asignificant portion of centripetal forces on the chamber 50. In someembodiments, the chamber 50 (which may include the inlet and outletpaths 65, 70) may be disposable, as will be described in more detailbelow. In some embodiments, such as illustrated in FIG. 7, the chamber50 is disposable and made of a polymeric material which may be flexible(e.g., a “bag chamber”). Therefore, the chamber holder 75 may beparticularly useful where the chamber 50 is disposable, as the chamber50 (on its own) may not be able to take the loads experienced when therotor 45 and chamber 50 is rotating, especially at high speeds and/orfor a long period of time. The chamber holder 75 can have increasedrigidity or strength relative to the chamber 50.

The chamber holder 75 includes cavities 80 sized to matably receive thechamber 50 and the associated inlet and outlet paths 65, 70 (where used)when the chamber holder 75 holds the chamber 50. Turning to FIGS. 6 and7, the chamber holder 75 and/or the rotor 45 may include a hingeassembly 85 located on or near the rotor 45 such that the chamber holder75 can be rotated to open and close over or under the chamber 50. Inthis regard, the chamber holder(s) 75 may be configured to releasablyenclose the chamber(s) 50. At least one locating pin 90 may be locatedon or near the rotor 45, with the pin(s) 90 configured to mate withcorresponding aperture(s) 95 in the chamber holder 75. In someembodiments, the pin(s) 90 can be located on the chamber holder 75 andthe corresponding apertures 95 can be located on or near the rotor 45.The chamber holder 75 may also include at least one lock 100 configuredto mate with corresponding aperture(s) 105 located on or near the rotor45. In some embodiments, the lock(s) 100 may be on or near the rotor 45and the corresponding aperture(s) 105 may be located on the chamberholder 75. Referring back to FIG. 5B, the chamber holder 75 may includea top shell 75 ₁ and a bottom shell 75 ₂. In some embodiments, thebottom shell 75 ₂ may be mounted to or integrated with the rotor 45 andthe top shell 75 ₁ may be configured to open and close. In otherembodiments, the top shell 75 ₁ may be mounted to or integrated with therotor 45 and the bottom shell 75 ₂ may be configured to open and close.In these embodiments, the pin(s) 90, aperture(s) 95, and/or lock(s) 100may be located on either the top shell 75 ₁ or the bottom shell 75 ₂.

Referring back to FIGS. 3 and 4, at least one chamber 50 may be attachedto or mounted on or held by the rotor 45. In the illustrated embodiment,four chambers 50 are attached to or mounted on the rotor 45. In otherembodiments, any number of chambers 50 may be attached to or mounted onthe rotor 45. Also, in the illustrated embodiment, a chamber holder 75has been rotated closed to cover each of the chambers 50. The chamberholders 75 may include a window 110, which may allow an operator to viewor allow visual access to the interior of the chamber 50. Although shownas two pieces 75 ₁, 75 ₂ in FIG. 5B, the chamber holder 75 may comprisea single piece or more than two pieces to hold a respective chamber 50.

Turning to FIG. 8, at least a portion of an umbilical assembly 120extends through the aperture 40 of the flange 35. The umbilical assembly120 can include a curvilinear umbilical guide or guide tube 125, whichcurves around or extends about the outer periphery of the rotor 45 andenters into and/or connects to a drum at the rear side of the rotor 45,as described in more detail below. The guide 125 is typicallyconstructed of a relatively strong material, such as aluminum or steel,to provide strength to the umbilical assembly 120 such that theumbilical assembly 120 can be “spun” about the same axis as the rotor45, as described in more detail below. In various embodiments, the guide125 may extend all the way through the aperture 40 of the flange 35, mayextend to the aperture 40, or may terminate before reaching the aperture40, as illustrated in FIG. 8.

Umbilical assemblies described herein may include a flexible conduitresiding in the guide tube 120. First and second elongate channels orpassageways for each chamber 50 extend through the conduit. The firstchannel or passageway is in fluid communication with the inlet 55 of arespective chamber 50 and the second channel or passageway is in fluidcommunication with the outlet 60 of the respective chamber 50. Thechannels or passageways (i.e., all the channels or passageways in theconduit) are preferably held in a spaced-apart relationship relative toone another, as will be described in more detail below. As used herein,the terms “channel” and “passageway” are interchangeable in thiscontext.

As illustrated in FIG. 8, for example, the umbilical assembly 120 caninclude a flexible conduit 130 mounted within and extending along thelength of the umbilical guide 125. In other words, the conduit 130 canreside within the umbilical guide or guide tube 125. The conduit 130 maycomprise a convoluted tube which provides suitable flexibility tobending and can also have high torsional rigidity or strength. Theconduit 130 preferably has a sufficiently long fatigue life that canwithstand continual flexing associated with centrifugal operation; anexemplary conduit 130 is type FPI available from Flexicon Limited,Birmingham, England, constructed of a modified Polyamide 12. The conduit130 may be corrugated flexible conduit. The conduit 130 may have anyinside diameter and any outside diameter suitable to accommodate theother components of the umbilical assembly 120, described below. In someembodiments, the conduit 130 may have inside diameter of about 35.5millimeters and an outside diameter of about 42.5 millimeters. In someembodiments, grease or another lubricous material is provided betweenthe umbilical guide 125 and the conduit 130 to reduce frictiontherebetween.

The aforementioned channels or passageways of the umbilical assembly 120can be or include first and second flexible tubes 135 for each chamber50. The tubes 135 may be constructed of any flexible material such asany flexible polymer including, but not limited to, PVC. The tubes 135are mounted within and extend along the length of the conduit 130. Oneof the tubes 135 of each chamber 50 can connect with the inlet 55 of thechamber 50 (or, where used, the inlet path 65 of the chamber 50) and theother can connect with the outlet 60 of the chamber 50 (or, where used,the outlet path 70 of the chamber 50) (see FIG. 5A). In the illustratedembodiments, umbilical assembly 120 includes eight flexible tubes 135,wherein two of the tubes 135 connect with each of the four chambers 50.The conduit 130 and the tubes 135 extend through the aperture 40 of theflange 35, regardless of whether the umbilical guide 125 extends thatfar. In other words, the flexible conduit 130 and the tubes 135 thereinextend from a location that is external to the enclosure or housing 15,through the access aperture 40, and into the internal cavity 44. Thetubes 135 may have any inner diameter and any outer diameter suitable tofit an appropriate number of tubes 135 within the conduit 130, which mayalso include potting material therein, as described in more detailbelow. In some embodiments, the tubes 135 may have an inner diameter ofabout ¼ inch and an outer diameter of about ⅜ inch (e.g., where theconduit 130 has the dimensions described above, and where eight tubes135 are employed).

Referring to FIGS. 9A and 9B, in some embodiments, the umbilicalassembly 120 includes a flexible center member 140 mounted within andextending along the length of the conduit 130. The flexible member 140extends substantially along a centerline of the conduit 130, and theflexible tubes 135 form an array and surround the flexible member 140.The flexible member 140 may comprise a “dummy tube,” similar to thetubes 135, but not in fluid communication with any of the chambers 50.In other embodiments, the flexible member 140 may be a tube with an opencavity having the same or smaller or larger diameter than the tubes 135,or may be solid tube, for example of polymeric material. For example,the flexible member 140 may comprise a tube having an inner diameter ofabout ⅜ inch and an outer diameter of about 9/16 inch, and the tubes 135may have an inner diameter of about ¼ inch and an outer diameter ofabout ⅜ inch. Where the flexible member 140 comprises a tube, the insideof the tube may include potting material, as described in more detailbelow. In some other embodiments, the flexible member 140 comprises atube configured to have fluid flow through the tube. The fluid mayprovide additional cooling to the umbilical assembly 120, for example.

The umbilical assembly 120 may also include potting material 145 withinthe conduit 130. The potting material 145 can separate the tubes 135from the conduit 130, can separate the tubes 135 from each other, and/orcan separate the tubes from the flexible member 140, where used. Morespecifically, the potting material 145 may be configured to hold thetubes 135 in a spaced-apart relationship relative to one another and/orhold the tubes 135 in a spaced-apart relationship relative to theconduit 130 and/or hold the tubes 135 in a spaced-apart relationshiprelative to the flexible member 140, where used. The potting material145 can be useful in restricting movement (e.g., twisting) of the tubes135 relative to one another during operation, as described in moredetail below. In other words, the potting material 145 can “lock” thetubes 135 and/or the conduit 130 together so that the tubes 135 areinhibited from moving relative to one another and/or relative to theconduit 130. As used herein, “potting material” includes any solidflexible material that substantially fills the internal volume of theconduit and surrounds the tubes and/or flexible center member. Thepotting material 145 can be any suitable material, including a polymersuch as polyurethane, for example. An exemplary potting material is F-25flexible polyurethane, available from BJB Enterprises, Inc., Tustin,Calif.

As will be discussed in more detail below, the conduit 130 has oppositeproximal and distal ends 130 ₁, 130 ₂. In some embodiments, the proximalend 130 ₁ of the conduit 130 and the tubes 135 contained therein extendthrough the access aperture 40. As illustrated in FIG. 9B, the proximalend 130 ₁ of the conduit 130 may include a flange 132 through which thetubes 135 extend. Where potting material is employed, the flange 132 mayassist in housing the potting material in the conduit 130. The flange132 may also assist in proper positioning of the conduit 130 with thetubes 135 contained therein. For example, the flange 132 may be situatedon the outside of the aperture 40 (e.g., on the outside of the enclosure15); the flange 132 may therefore allow an operator to position theproper length of conduit 130 in the interior cavity 44.

Referring now to FIGS. 10-12, the umbilical assembly 120 curves aroundor extends about the outer periphery of the rotor 45 and enters a drum150 at the rear side of the rotor 45. In some embodiments, a portion ofthe umbilical assembly 120 connects with the drum 150. In theillustrated embodiment, a drive mechanism 155 is driven by a motor 160and a belt 165. The drive mechanism 155 may include various gears 170,at least some of which may be located within the drum 150. In particularembodiments, the drive mechanism 155 causes the umbilical assembly 120to rotate about an axis at speed X, and causes the rotor 45 to rotateabout the same axis at speed 2X or about speed 2X. In other words, theumbilical assembly 120 rotates at one-half or about one-half the speedof the rotor 45. In some embodiments, the drum 150 is driven at speed Xby the motor 160 (the umbilical assembly 120 in turn rotates at speedX), and the drive mechanism 155 includes gearing which causes the rotor45 to rotate at speed 2X or about speed 2X.

FIG. 13 illustrates an exemplary arrangement and shape of the umbilicalassembly 120. The conduit 130 has opposite proximal and distal ends 130₁, 130 ₂. In some embodiments, the proximal end 130 ₁ of the conduit 130and the tubes 135 contained therein extend through the access aperture40 (see FIGS. 15 and 16, for example). The distal end 130 ₂ of theconduit 130 extends through the drum 150 and may connect to the rotor 45to thereby allow the tubes 135 to be fluidly connected with the chambers50. In some embodiments, and as illustrated, the conduit distal end 130₂ includes a coupling 133. The coupling 133 can couple the conduit 130to the rotor 45 and therefore allow the tubes 135 to be fluidlyconnected with the chambers 50. In some embodiments, the coupling 133has a hexagonal shape, although other shapes are contemplated, includingother polygonal shapes.

In this configuration, the coaxial half-speed rotation of the umbilicalassembly 120 inhibits the tubes 135 of the umbilical assembly 120 frombeing completely twisted during rotation of the rotor 45. The completescientific explanation for this phenomenon can be found in, for example,U.S. Pat. No. 3,586,413 to Adams, the disclosure of which is herebyincorporated by reference herein in its entirety. To summarize, if therotor 45 has completed a first 360° rotation and the umbilical assembly120 a 180° half-rotation in the same direction, the tubes 135 of theumbilical assembly 120 will be subjected to a 180° twist in onedirection. Continued rotation of the rotor 45 for an additional 360° andumbilical assembly 120 for an additional 180° will result in the tubes135 of the umbilical assembly 120 being twisted 180° in the otherdirection, returning the tubes 135 to their original untwistedcondition. Thus, the tubes 135 of the umbilical assembly 120 may besubjected to a continuous partial twist or flexure or bending duringoperation but are never completely rotated or twisted about their ownaxis.

This solution can provide advantages over typical continuous flowcentrifuges. In conventional mechanisms, when a length of tubing isfixedly attached to the rotation axis of a device which contains thefluid material to be centrifuged, the entire length of tubing must berotated by use of rotating seals or other means to avoid twisting thetubing. However, these seals too frequently become the source of leaksand/or contamination.

In contrast, the umbilical assembly 120 of the present inventionprovides a transition from the “rotating world,” including the rotor 45,to the “stationary world,” such as that area outside the enclosure 15.Rotary unions and seals are not required, providing a sterile andcompletely closed system. Other advantages can include the use ofdisposable components that can be easily replaced, resulting in sterilepaths, as described in more detail below.

Umbilical-like arrangements for use with continuous flow centrifugeshave been disclosed in, for example, U.S. Pat. Nos. 4,216,770,4,419,089, 4,389,206, and 5,665,048. However, these solutions do notadequately address the high stresses and strains imparted on the tubesdue to the g-forces created by rotating the centrifuge at high speedsand/or due to the continuous fluid flow necessary to substantiallyimmobilize particles. Moreover, rotating the centrifuge at high speedscreates increased torque of the umbilical system and the tubes containedtherein, and the arrangements disclosed to date do not allow theumbilical system and the tubes contained therein to be rotated at a highrate of speed for an acceptable amount of time before failing. In otherwords, it is believed that the aforementioned solutions simply do notallow the systems to be “scaled up” to an appreciable degree and do notallow the system to be rotated at high rates of speed without rapid andcatastrophic failure of the tubing system. This is the case, at least inpart, because the friction increases as the speed and the scaleincrease, producing an increased torque of the umbilical system.

The present invention addresses these deficiencies by providing a morerobust umbilical assembly that can withstand higher rotational speeds(and therefore higher g-forces), allowing a system, such as a continuousflow centrifuge, to be “scaled up” to larger sizes without subjectingthe umbilical assembly to immediate or rapid catastrophic failure. Thisis due to the configuration of the umbilical assemblies of the presentinvention, such as the umbilical assembly 120 illustrated in FIGS. 8-14.

In this configuration, excessive twisting of the tubes 135 is inhibitedduring operation (i.e., while the rotor is rotated about the axis atspeed 2X and the umbilical assembly is rotated about the axis at speedX). More particularly, excessive twisting of the tubes 135 relative toone another and relative to the conduit 130 is prevented. Put anotherway, the tubes 135 and the conduit 130 are effectively “locked” together(e.g., by use of the potting material 145), thereby inhibiting relativemovement of the components. In addition, excessive rubbing of tubes 135against each other and against the conduit 130 is reduced, if nottotally prevented. The result is a tubing system that can experience arelatively long life in a large-scale system that is rotated about theaxis at a high rate of speed.

This is accomplished, in part, by restricting the movement of the tubes135 within the conduit 130. The potting material 145 can maintain thetubes 135 in place, and thereby prevent the tubes 135 from excessivetwisting relative to the conduit 130. In other words, the pottingmaterial 145 can “lock” the tubes 135 and/or the conduit 130 together,thereby inhibiting movement of the tubes 135 relative to one anotherand/or relative to the conduit 130. The potting material 145 can alsoprovide a buffer between the individual tubes 135, thereby preventingthe tubes 135 from rubbing against one another. Moreover, the pottingmaterial 145 can provide a buffer between the tubes 135 and the conduit130, thereby preventing the tubes 135 from rubbing against the conduit130 during operation. Rubbing of these components can not only causecontinual stress, but can also generate heat, further weakening thecomponents.

Moreover, where used, the flexible member 140 can serve to maintain thetubes 135 in an organized array around the flexible member 140, furtherreducing twisting of the tubes 135. Where potting material 145 isemployed, the potting material 145 can serve to “lock” the conduit 130,the tubes 135, and/or the flexible member 140 together, therebyinhibiting movement of the components relative to one another. Moreover,the potting material 145 may serve as a buffer between the tubes 135 andthe flexible member 140, thereby preventing the tubes 135 from rubbingagainst the flexible member during operation. Rubbing of thesecomponents can not only cause continual stress, but can also generateheat, further weakening the components.

Selection of an appropriate material for the conduit 130 can preventfailure thereof due to rubbing against the umbilical guide 125 duringoperation. Furthermore, grease or other lubricous material can beapplied between the conduit 130 and the guide 125 to further reducefriction and potential failure of the conduit 130 and/or the tubes 135during operation (e.g., fatigue failure of the conduit 130). Moreover,the inside of the guide 125 can be polished (e.g., mechanicallypolished) to further reduce friction between the conduit 130 and theguide 135. Additionally or alternatively, the inside of the guide 125and/or the outside of the conduit 130 can be coated with a lubricousmaterial, such as Teflon®, to reduce friction between the twocomponents.

Using these configurations, a system, such as a continuous flowcentrifuge without use of rotary seals or the like, has beensuccessfully “scaled-up” as follows. The rotor and the chamber(s) can berotated at speeds of at least 3000 RPM. This corresponds to a g-force ofabout 1000 g at the chamber (e.g., at ⅓ the height of the chamber “cone”or ⅓ chamber height from the “tip” of the chamber). The fluid flow ratesthrough each chamber can be at least 1 liter/minute. Thus, where fourchambers are employed, for example, the total flow rate can be at least4 liters/minute. The volume of each chamber can be at least 1 liter.Thus, where four chambers are employed, for example, the total chambervolume can be at least 4 liters. Of course, lower rotational speeds,flow rates, and/or chamber volumes can be employed for variousoperations (e.g., the rotational speed of the rotor can range from0-3000 RPM and/or the fluid flow rate through each chamber can rangefrom 0-1 liters/minute and/or the volume of each chamber can be lessthan 1 liter). Moreover, it is believed that the aforementionedembodiments and the alternative embodiments disclosed below can allowfor a robust system that is “scaled-up” to an even higher degree (e.g.,rotational speeds higher than 3000 RPM, flow rates higher than 1liter/minute per chamber, chamber volumes greater than 1 liter, etc.).More specifically, it is believed that the aforementioned embodimentsand the alternative embodiments disclosed below can allow for a robustsystem that employs rotation speeds of about 10, 25, 50, 100, 250, 500,750, 1000, 1250, 1500, 1750, 2000, 2500, 3000, 5000, or 10,000 RPM ormore or any subrange therein; it is also believed that theaforementioned embodiments and the alternative embodiments disclosedbelow can allow for a robust system that can produce and withstandg-forces of about 10, 25, 50, 100, 250, 500, 750, 1000, 1250, 1500,1750, 2000, 2500, 3000, 5000, or 10,000 g or more or any subrangetherein. Likewise, it is believed that the aforementioned embodimentsand the alternative embodiments disclosed below can allow for fluid flowrates of about 0.0001, 0.001, 0.01, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5,1.75, 2, 2.5, 3, 5, 10, 20, 25, or 50 liters/minute per chamber or moreor any subrange therein; it is also believed that the aforementionedembodiments and the alternative embodiments disclosed below can allowfor individual chamber volumes of about 0.0001, 0.001, 0.01, 0.1, 0.25,0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 5, 10, 20, 25, or 50 liters ormore or any subrange therein.

Other embodiments of the umbilical assembly 120 are contemplated. Forexample, the flexible member along the centerline of the conduit can beomitted. One of the tubes may extend substantially along a centerline ofthe conduit, with the remaining tubes forming an array and surroundingthe center tube. In this regard, the center tube takes the place of the“dummy tube,” and it connects with either the inlet or outlet path ofone of the chambers. Potting material may be provided to preventtwisting and rubbing, as described in more detail above.

In still other embodiments, potting material is not required. Forexample, the umbilical assembly could comprise one solid extrusion witha plurality of channels or passageways extending therethrough. Eachchannel or passageway would connect with either an inlet or an outlet ofone of the chambers. The solid extrusion may be flexible, and may becontained within a guide to provide strength, such as the guide 120described above.

An exemplary solid extrusion assembly 330 is illustrated in FIG. 21. Thesolid extrusion assembly 330 may form part of the umbilical assembly 120described herein. More specifically, the solid extrusion assembly 330may take the place of the conduit 130 and the tubes 135 (as well as thepotting material 145 and/or the flexible member 140 where thesecomponents are used) in all embodiments described above and below. Thus,it will be understood that the solid extrusion assembly 330 may fitwithin the guide tube 125 and define the conduit with spaced-apartelongate passageways therein.

Still referring to FIG. 21, the solid extrusion assembly 330 includes asolid extrusion 330 e. The solid extrusion is flexible with an outerwall and internal elongate channels or passageways 335 that define thespaced-apart passageways. Similar to the tubes 135 described in detailherein, the passageways 335 are in fluid communication with thechamber(s) 50. In particular, one passageway 335 is in fluidcommunication with the inlet 55 of a respective chamber 50 and another,different passageway 335 is in fluid communication with the outlet 60 ofthe respective chamber 50. In the illustrated embodiment, the solidextrusion 330 e includes eight passageways 335, and is thereforeconfigured for use with four chambers 50. The extrusion 330 e mayinclude greater or fewer than eight passageways 335 as needed.

As explained above, the extrusion assembly 330 may take the place of atleast the conduit 130 in the umbilical assembly 120. Any differencesbetween the extrusion assembly 330 and the conduit 130 will now bedescribed.

As described above, the passageways 335 generally take the place of theflexible tubes 135. However, unlike the tubes 135, the passageways 335may not extend all the way to the chamber(s) 50 and/or all the way toconnection points outside the enclosure 15 (see FIGS. 15 and 16). Thus,in some embodiments, connectors (such as barbed connectors) may beincluded or used at one or both ends of each passageway 335. Connectorsat a distal end of the passageways 335 may allow for tubing (which maybe similar to the flexible tubing 135 described herein) to connect thepassageways 335 with the inlet 55 and outlet 60 of the chamber(s) 50 (orthe flange inlet and outlet paths 65, 70, where used). Similarly,connectors at a proximal end of the passageways 335 may allow for tubing(which may be similar to the flexible tubing 135 described herein) toconnect the passageways 335 with components outside the enclosure 15,such as pumps or other tubing, which are described in more detail below.

In some embodiments, and as illustrated, the solid extrusion assembly330 includes a sheath 330 s. The sheath 330 s material and configurationmay have similar properties and provide similar advantages to theconduit 130 material and configuration described above. In particular,the sheath 330 s may help withstand friction with the guide tube 125and/or may help transfer torque during operation. In some embodiments,the sheath 330 s may include ridges to minimize contact area with theguide tube 125 and/or to minimize friction during operation. The sheath330 s may be adhered to or may snugly fit around an outer wall of thesolid extrusion 330 e. In some embodiments, the sheath 330 s and thesolid extrusion 330 e are sized and configured such that there is aninterference fit (perhaps a substantial interference fit) between thetwo components. In this regard, the sheath 330 s and the solid extrusion330 e may act as a single unit during operation (i.e., as the extrusionassembly 330). In some embodiments, the sheath 330 s and the solidextrusion 330 e may be integrated, and in some embodiments the sheath330 s may be omitted.

The solid extrusion assembly 330 may provide the same or substantiallythe same advantages as the conduit 130, tubes 135, and potting material145 as described in detail above. Briefly, the passageways 335 may bepositioned in the solid extrusion 330 e such that they are spaced-apartfrom one another and/or from an outer wall of the extrusion 330 e and/orfrom the sheath 330 s, where used. The spaced-apart relationship may bemaintained during operation, and therefore may help minimizemovement/twisting of the passageways 335 relative to one another and/ormay help minimize movement/twisting of the passageways 335 relative tothe sheath 330 s, where used. The result is a more robust umbilicalassembly that can be used in “scaled-up” operations, as described inmore detail above.

The solid extrusion 330 e may comprise polymeric material, such as PVC,platinum-cured silicon, C-Flex, and other similar materials. The sheath330 s, where used, may comprise materials similar to those describedabove with regard to the conduit 130.

Again, to avoid repetition, the embodiments described above and belowwill only be described with the umbilical assembly 120 including theconduit 130 and the tubes 135 (and optionally the potting material 145and/or the flexible member 140). However, it will be understood that theumbilical assembly 120 may include the extrusion assembly 330 or simplythe extrusion 330 e in place of the conduit 130, the tubes 135, and/orthe potting material 145.

In some embodiments, and as illustrated in FIGS. 14A-D, a funnel 180 isprovided on the rear side of the flange 35 and/or the door 20. Thefunnel 180 includes an opening 185 opposite the aperture 40. The funnel180 is configured to accept at least part of the umbilical assembly 120.In the illustrated embodiments, the funnel 180 accepts the conduit 130,with the tubes 135 contained therein. The conduit 130 passes through theopening 185 and the aperture 40 such that at least the tubes 135 extendthrough the aperture 30. The tubes 135 can then be connected toadditional components, as described in more detail below.

The funnel 180 can provide for reduced strain/stress on the conduit 130and the tubes 135 where the conduit makes a final bend before extendingthrough the aperture 30. In this regard, the funnel 180 provides acontrolled bend of the conduit 130 and tubes 135 contained therein. Thiscan reduce the chance of failure of the conduit 130 and/or the tubes 135at what otherwise would be a high stress concentration point. Thecenterline of the opening 185 is preferably aligned or substantiallyaligned with the axis of rotation of the umbilical assembly 120;otherwise, additional, unnecessary loads could be applied to the conduit130 and/or the tubes 135. Also, the funnel 180 preferably has a bendradius that is greater than the minimum dynamic bend radius of theconduit 130.

Moreover, the shape of the funnel 180 provides for a consistent bend ofthe conduit 130 and the tubes 135 contained therein while the umbilicalassembly 120 is rotating during operation. The funnel 180 may bemachined and/or polished to reduce friction or rubbing while the conduit130 is rotating within the funnel 180. In addition, grease or otherlubricous material may be applied to the funnel 180 to further reducefriction or rubbing. Additionally or alternatively, the funnel and/orthe outer surface of the conduit 130 may be coated with a lubricousmaterial such as Teflon® to reduce friction or rubbing.

Turning now to FIGS. 15 and 16, the conduit 130 and the tubes 135 areseen protruding from the aperture 40. At least one pump 200 may beprovided on the enclosure 15 or on a panel thereon, or may be providedaway from the enclosure 15. At least one valve may be provided on theenclosure 15 or on a panel thereon, or may be integrated with the tubingshown on the right side of the enclosure 15, or may be provided awayfrom the enclosure 15. For example, one or more pinch valves may beprovided on the enclosure 15, with the pinch valves configured to allowtubing to be inserted therethrough such that the tubing can be squeezed(or pinched) closed or partially closed.

FIG. 17 illustrates an exemplary flow diagram of the system. The systemmay include two sets: the chambers/umbilical set and the valve/fluidpath set. The chambers/umbilical set may include at least the chamber(s)50, the conduit 130, and the tubes 135 within the conduit 130. In theillustrated embodiment, the tubes 135 in fluid communication with theinlet paths 65 of the chambers 50 may connect with the pump 200 (seealso FIGS. 15 and 16). Also in the illustrated embodiment, the tubes 135in fluid communication with the outlet paths 70 of the chambers 50 mayconnect with at least one return tube 205 (see FIGS. 15 and 16). On theopposite side of the pump 200, tubes 210 may connect with a harness ormanifold 215, which connects the chambers/umbilical set with thevalve/fluid path set. In some embodiments, the two disposable sets canbe connected by a sterile tube welding process. The disposable sets canbe supplied sealed and/or sterilized. By employing a sterile tubewelding process, the disposable sets can be connected without using anysort of connector (e.g., harness, manifold, etc.), and the disposablesets do not need to be “opened,” which could result in a loss ofsterility.

The valve/fluid path set typically comprises tubing and/or valves, whichmay be integrated with the tubing. In some embodiments, the valve/fluidpath set is configured to be routed through one or more valves, such aspinch valves included on the enclosure, for example. In the embodimentillustrated in FIGS. 15 and 16, the valve/fluid path set includes thetubing seen on the right side of the enclosure 15. In some embodiments,the valve/fluid path set includes the return tube(s) 205. It is notedthat, although the tubes are shown as “broken” in FIGS. 15 and 16, thetubes 135 protruding from the aperture 40 of the flange 35 willtypically connect with the pump 200 and/or the return tube(s) 205. Thereturn tube(s) 205 and/or the tubes 135 running to the pump 200 may berouted through the handle 30 of the door 20 and/or kept in place by oneor more holders 220, such as hooks.

As seen in the flow diagram of FIG. 17, the valve/fluid path set canconnect to various containers, such as a bioreactor 230, a waste mediacontainer 235, a clean media container 240, and/or a cell harvestcontainer 245. The various containers will typically be located awayfrom the enclosure 15, although at least some of the containers may becontained within the enclosure 15 in some embodiments. In the embodimentillustrated in FIGS. 15 and 16, the lower (open) portions of the tubeson the right side of the enclosure 15 may connect with variouscontainers, such as the containers described above. The valve/fluid pathset may be configurable to perform various operations, as will besummarized in more detail below. At least one secondary pump 250 may beincluded on the enclosure 15 or away from the enclosure 15; thesecondary pump 250 may be useful in at least some of these variousoperations.

At least some of the components described herein may be disposable. Forexample, the chambers 50, the conduit 130, and/or the tubes 135contained therein may be disposable. As described above, the disposablechambers 50 may be constructed of a flexible or resilient polymer, suchas a transparent or translucent polymer, thereby forming a “bagchamber.” In some embodiments, the disposable chambers 50 may bethermoformed. In some embodiments, the material of the disposablechambers 50 may be relatively thin (e.g., less than 1 mm thick medicalgrade PVC). In other embodiments, the material of the disposablechambers 50 may be another material (e.g., FEP, C-Flex, blow molded EVA,low-density polyethylene, etc.), to permit compliance with goodmanufacturing practice (cGMP). The disposable chambers 50 may includeinlet and outlet fluid paths 65, 70 (which may be integrated), asillustrated in FIG. 5A, and as described in more detail above. Thechamber holders 75 (see FIG. 5B) can inhibit failure of the disposablechambers 50 by accommodating the majority of or all of the loadsexperienced due to rotation of the rotor 45 and the chambers 50.

A system comprising two separate disposable fluid paths is alsocontemplated. In this system, the two sets described above (i.e., thechambers/umbilical set and the valve/fluid path set) may be separatelydisposable. For example, referring to FIGS. 15-17, the chambers 50, theconduit 130, and the tubes 135 contained therein (leading up to orextending just past the pump 200) may comprise a first disposable flowpath (Set #1). The tubing and/or valves to the right of the harness ormanifold 215 may comprise a second disposable flow path (Set #2). Thereturn tube(s) 205 will typically be included in disposable Set #2, butmay be included in either disposable flow path.

The disposable fluid path(s) can provide advantages over conventionalcontinuous flow centrifuges and like apparatus. Systems that do notemploy disposable flow paths generally have to adhere toCleaning-in-Place (CIP) and Sterilization-in-Place (SIP) procedures andstandards. This is especially the case for those systems that performoperations that are sensitive to contamination, such as cellculturing/harvesting and blood processing, for example. The disposableflow paths described herein can eliminate the need to perform CIP andSIP procedures. Furthermore, the use of completely disposable fluidpaths permits compliance with good manufacturing practice (cGMP). Thepaths can be provided as sterile components ready for insertion and use.

As discussed above, the systems disclosed herein can be used to performa number of processing, harvesting, etc. methods and operations.Exemplary methods and operations are disclosed in detail in co-pendingand commonly owned International Application Nos. PCT/US2009/004113(International Publication No. WO 2010/008563) and PCT/US2009/004137(International Publication No. WO 2010/008579), both filed Jul. 16,2009, the disclosures of each of which are hereby incorporated byreference herein in their entirety. A brief overview of some of themethods and operations follow, with reference to FIG. 17.

In continuous flow centrifugation operations, media containing particlessuch as cells will be fed in the rotating chambers 50 to form afluidized bed of cells. After the chambers 50 are filled with cells, theflow will be reversed to empty out the chambers 50. The system (i.e.,the rotors and the chambers) does not need to stop rotating throughoutthis application. The cycle can be repeated to concentrate cells fromlarge volumes.

Similarly, in perfusion operations, particles such as cells areimmobilized in the rotating chambers 50 in fluidized beds for culturingand/or harvesting. For example, cells and media may be removed from thebioreactor 230 and transported to the chambers 50. A continuous flow ofmedia and cells substantially opposes the centrifugal force created bythe rotating chambers 50, thereby immobilizing the cells in a fluidizedbed. Using a perfusion cycle, the cells are provided with fresh mediacontinuously and spent media is removed, such as to the waste container235. The cells can then be removed from the chambers 50, perhaps byreversing the fluid flow and returning the cells to the bioreactor 230or the cell harvest container 245.

The systems disclosed herein can also perform media exchanges duringcell culture or harvest. In this application, cell culture is first fedto the rotating chambers 50 to form a bed of fluidized cells, and then anew media or buffer is fed through the inlet paths 65 of the chambers 50to be perfused through the bed. For example, the new media or buffer maybe introduced from the clean media container 240. After the cells arewashed with the media or buffer, the chambers 50 are emptied out byreversing the flow (i.e., introducing media to the outlet paths 70 ofthe chambers 50). It is noted that the media/buffer exchange applicationcould be used prior to additional processes such as transfection, celldispensing, seeding a bioreactor, etc.

The systems are also capable of separating population of cells based ondensity and/or size. In this application, fluid containing differentpopulations of cells will be fed into the rotating chambers 50. Cellswill be separated by modulating the fluid feed rate and/or thecentrifugal force (i.e., the rotational speed of the rotor). Once thefluid feed rate and centrifugal forces are adjusted appropriately,lighter/smaller cells will exit out of the chambers 50 with media. Aftera cell bed is formed, fresh media or buffer could be used to separateanother population by once again adjusting the feed rate and/orcentrifugal force. This process can be repeated several times toseparate multiple populations of cells that differ by density and/orsize. Finally heavier/larger cells are harvested by reversing the flowof fresh media.

These are just a sampling of the processes that can be performed by thedisclosed systems. Other processes include cell dispensing,transfection, eletroporation, selection/purification/enrichment (such asby using affinity matrices), fractionation of proteins/biomaterials,associating particles with and/or removing particles from scaffoldingmaterial, and coating particles. These processes are described in detailin the aforementioned applications.

Referring again to FIGS. 15 and 16, a display 260 may be provided on theenclosure 15, or may be provided on a panel attached or adjacent to theenclosure 15, or may be provided away from the enclosure 15. The display260 is connected (e.g., directly or wirelessly) to at least onecontroller (not shown). There may be controllers associated with thevarious components of the system, including the motor, the pump(s), thevalves, etc. There may be one controller associated with all componentsor certain components may have dedicated controllers.

Simulated screenshots of the display 260 are illustrated in FIGS. 18-20.The display 260 may allow parameters to be entered and data or progressto be read by an operator. The display may include touch screen buttonsthat dictate the operation of various components, as seen in FIG. 18. Insome embodiments, there is a separate user input device such as akeyboard; in other words, the display may not employ a touch screen.

In some embodiments, a light source and/or a camera may be included onthe enclosure or in the interior cavity of the enclosure. The lightsource and/or the camera may be useful to illuminate the chamber(s)and/or capture images of the chamber(s) (e.g., the interior of thechamber(s) during operation). The captured images may be useful toprovide feedback to the operator and/or the system as to the progress ofthe particular process taking place within the chamber(s). The cameramay be in communication with the display (either directly or via acontroller), such that the images may be transmitted to the display, forexample. The controller(s) and/or software associated with thecontroller(s) may automatically correlate captured images with aparticular chamber.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. The invention is defined by the following claims, withequivalents of the claims to be included therein.

1. An apparatus for manipulating particles, the apparatus comprising: arotor rotatable at a speed about an axis, the rotor having an outerperiphery and front and rear opposite sides; at least one chambermounted on the rotor, each chamber having an inlet and an opposedoutlet; an umbilical assembly rotatable about the axis, the umbilicalassembly comprising: a curvilinear guide connecting to the rear side ofthe rotor; a flexible conduit residing in the guide; and first andsecond elongate passageways for each chamber extending through theconduit, wherein the first passageway is in fluid communication with theinlet of a respective chamber and the second passageway is in fluidcommunication with the outlet of the respective chamber; and a drivemechanism configured to rotate the umbilical assembly at about one-halfthe speed of the rotor; wherein each chamber comprises a substantiallyconical body portion and a flange extending about at least a portion ofa perimeter of the conical body portion, the flange including an inletfluid path that is external to the conical body portion and extendsaround at least a portion of the perimeter of the conical body portionto the chamber inlet and an outlet fluid path that extends from thechamber outlet, and wherein the first elongate passageway is in fluidcommunication with the flange inlet fluid path and the second elongatepassageway is in fluid communication with the flange outlet fluid path.2. The apparatus of claim 1, wherein the first and second passagewaysfor each chamber comprise corresponding first and second flexible tubes.3. The apparatus of claim 2, wherein the first tube connects with theflange inlet fluid path of a respective chamber and the second tubeconnects with the flange outlet fluid path of the respective chamber. 4.The apparatus of claim 1, wherein each chamber is a translucent ortransparent fluid chamber.
 5. The apparatus of claim 1, wherein eachchamber is disposable.
 6. The apparatus of claim 1, wherein the drivemechanism comprises gears.
 7. The apparatus of claim 1, wherein thecurvilinear guide is configured to extend about the outer periphery ofthe rotor.
 8. The apparatus of claim 1, wherein the inlet of eachchamber is at an apex of the conical body portion.
 9. The apparatus ofclaim 8, wherein the outlet of each chamber is proximate a base of theconical body portion.
 10. A method of manipulating particles, the methodcomprising: providing the apparatus of claim 1; rotating the rotor andthe at least one chamber at a first speed, thereby creating acentrifugal force field; rotating the umbilical assembly at a secondspeed, wherein the second speed is about one-half the first speed,thereby inhibiting the first and second passageways for each chamberfrom fully twisting; flowing media and particles into a respectivechamber using the first passageway, wherein a continuous flow of mediaand particles creates a fluid force that substantially opposes thecentrifugal force field, thereby immobilizing at least some of theparticles in a fluidized bed in the respective chamber; and flowingmedia out of the respective chamber and through the second passageway.11. A centrifugal fluid processing system, the system comprising: ahousing having an interior cavity with an access aperture extending froman external surface of the housing to the interior cavity; at least onechamber having an inlet and an opposed outlet held on a rotor in theinterior cavity; a substantially rigid curvilinear guide extendingaround an outer periphery of the rotor in the interior cavity; aplurality of elongate passageways in the guide, the plurality ofpassageways extending from a location that is external to the housingthrough the access aperture and into the interior cavity, wherein theplurality of passageways includes first and second passageways for eachchamber, and wherein the first passageway is in fluid communication withthe inlet of a respective chamber and the second passageway is in fluidcommunication with the outlet of the respective chamber; and a drivemechanism configured to rotate the guide at a first speed and the rotorand the at least one fluid chamber at a second speed, wherein the secondspeed is about twice the first speed.
 12. The system of claim 11,wherein each chamber comprises a substantially conical body portion anda flange extending about at least a portion of a perimeter of theconical body portion, the flange including an inlet fluid path that isexternal to the conical body portion and extends around at least aportion of the perimeter of the conical body portion to the chamberinlet and an outlet fluid path that extends from the chamber outlet. 13.The system of claim 12, wherein the first and second passageways foreach chamber comprise corresponding first and second flexible tubes. 14.The system of claim 13, wherein the first tube connects with the flangeinlet fluid path of a respective chamber and the second tube connectswith the flange outlet fluid path of the respective chamber.
 15. Thesystem of claim 12, wherein the inlet of each chamber is at an apex ofthe conical body portion.
 16. The system of claim 15, wherein the outletof each chamber is proximate a base of the conical body portion.
 17. Thesystem of claim 11, wherein: the at least one chamber comprises firstand second chambers; the first and second passageways for each chambercomprise first through fourth flexible tubes; the first tube is in fluidcommunication with the inlet of the first chamber and the second tube isin fluid communication with the outlet of the first chamber; the thirdtube is in fluid communication with the inlet of the second chamber andthe fourth tube is in fluid communication with the outlet of the secondchamber.
 18. The system of claim 11, wherein each chamber is disposable.19. The system of claim 11, wherein the drive mechanism comprises gears.20. The system of claim 11, further comprising an enclosure comprisingthe housing and a door coupled to the housing, wherein the door isconfigured to be moved between a closed position and all open position.21. The system of claim 20, wherein, in the open position, the doorprovides access to the interior cavity of the housing.
 22. The system ofclaim 21, further comprising a window on the door, wherein, in theclosed position, the window is configured to provide visual access tothe at least one chamber.
 23. The system of claim 20, further comprisinga display on the enclosure, the display configured to displayoperational data and/or parameters of the system.
 24. The system ofclaim 11, wherein each chamber is a translucent or transparent fluidchamber.